General and Stereoselective Method for the Synthesis of Sterically

Mar 29, 2017 - Development of a Scalable, Chromatography-Free Synthesis of t-Bu-SMS-Phos and Application to the Synthesis of an Important Chiral ...
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General and Stereoselective Method for the Synthesis of Sterically Congested and Structurally Diverse P‑Stereogenic Secondary Phosphine Oxides Zhengxu S. Han,* Hao Wu, Yibo Xu, Yongda Zhang, Bo Qu, Zhibin Li, Donald R. Caldwell, Keith R. Fandrick, Li Zhang, Frank Roschangar, Jinhua J. Song, and Chris H. Senanayake Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Old Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877, United States S Supporting Information *

ABSTRACT: A general and efficient method for the synthesis of bulky and structurally diverse P-stereogenic chiral secondary phosphine oxides (SPOs) by using readily available chiral amino alcohol templates is described. These chiral SPOs could be used as chiral building blocks for the synthesis of difficult-to-access bulky P-stereogenic phosphine compounds or ligands for organic catalysis.

ration of sterically demanding substituents (e.g., t-Bu) should be more facile, thus providing an alternative avenue for the synthesis of sterically hindered TPOs.6−9 Moreover, SPOs themselves have been found to be effective ligands for a number of transformations (nonenantioselective).10 Despite the wide range of potential applications of SPOs, their synthesis has met with limited success. Buono, Han, and co-workers have reported pioneering work on the asymmetric synthesis of SPOs by employing menthol as a chiral auxiliary (Scheme 1a).3c,5c Chemical and kinetic resolution are other means of preparation that have also been described recently,8 but only a limited scope of P-stereogenic SPOs has been prepared. Therefore, an effective asymmetric synthesis of chiral 3 entities with diverse structures needed to be developed in order to better understand the properties of SPOs and to further expand their synthetic utilities. Aiming to develop a practical and stereoselective SPO synthesis, we focused on using readily available chiral 1,2-amino alcohols as templates. On the basis of our previous work,3d we envisioned that the reaction of R1PCl2 with 7 would provide intermediate 8 in optically pure form (Scheme 1b). The more reactive P−N bond should selectively react with water to afford phosphinate 10 in a stereospecific fashion. The subsequent reaction of a nucleophile R2 M with 10 would afford the chiral nonracemic SPO. Herein, we report the development of a general and stereoselective method for the synthesis of structurally diverse, sterically demanding, P-stereogenic SPOs

P-Stereogenic chiral phosphines (P-SCPs, 1, Scheme 1) have been demonstrated as effective ligands in enantioselective Scheme 1. Strategies for Synthesis of Enantiomerically Enriched SPOs and Their Applications

organometallic catalysis.1 However, their development has been significantly hindered due to the synthetic challenges.2,3 PStereogenic chiral tertiary phosphine oxides (TPOs, 2, Scheme 1), on the other hand, are attractive precursors of P-SCPs due to their air- and moisture-stability and can be prepared in high chemical and optical purity.4 Elegant work has been carried out recently for the synthesis of certain types of 2, but the synthesis of sterically hindered variations, such as those containing a tertbutyl functionality, still remains a significant challenge.3,5 Secondary phosphine oxides (SPOs, 3, Scheme 1) are promising precursors of 2 since the P−H bond can be readily functionalized, thus offering a handle for differentiation. As SPOs are inherently less sterically demanding, the incorpo© 2017 American Chemical Society

Received: February 23, 2017 Published: March 29, 2017 1796

DOI: 10.1021/acs.orglett.7b00568 Org. Lett. 2017, 19, 1796−1799

Letter

Organic Letters

overall yield. As expected, reaction of Rp-18a with t-BuLi in THF at −80 °C provided highly enantiomerically enriched (S)3a in 78% isolated yield with the full recovery of template 16. Having identified the optimal reaction conditions, the scope of the synthesis of diastereomerically pure 18 was examined. The results in Table 1 show that a broad scope of H-

based on the above-mentioned concept. The application of chiral SPO in the synthesis of bulky P-stereogenic TPO under catalytic conditions is also described. To evaluate our strategy, (1R,2S)-norephedrine 11 was first used for the study. Recently, we reported that either Rp-13 or Sp-13 1,3,2-benzoxazaphosphinine-2-oxide is useful for the synthesis of P-stereogenic phosphine oxides (Scheme 2).3d The

Table 1. Substrate Scope for the Synthesis of P-Stereogenic SPOs Using (1S,2R)-Aminoindanol Derivative 16

Scheme 2. Stereochemistry and Synthesis of (S)-t-Bu(Ph)phosphine Oxide 3a Using 11 as Template

synthesis of 13 using PhP(O)Cl2 generally provided the Rpisomer preferentially, except when pyridine was used as base when the Sp-isomer was the major product but in low selectivity (63:37 dr). Later studies demonstrated that Sp-13 could be obtained in high selectivity (98:2 dr) by first treating 11 with PhPCl2 instead of PhP(O)Cl2 to yield Sp-12, followed by oxidation with t-BuO2H. Sp-13 is a crystalline product, and its enantiomerically pure form was obtained by recrystallization from EtOAc/hexanes. On the other hand, in situ treatment of Sp-12 with water afforded a stable crystalline product phosphinate Rp-14a in 98:2 dr, and its enantiomeric pure form was obtained via a single crystallization in 90% yield. The stereochemistry of Rp-14a was determined by single-crystal Xray crystallography. It was reasoned that Rp-14a was formed through Rp-15 that was obtained by nucleophilic addition of water on phosphorus by cleaving the active P−N bond via an SN2 mechanism. Interestingly, treatment of Rp-14a with t-BuLi gave a clean reaction and afforded the highly enantiomerically enriched SPO (S)-tert-butyl(phenyl)phosphine oxide 3a5c in good isolated yield with full recovery of 11. Encouraged by the above results, the potential of other chiral amino alcohols as auxiliaries for the synthesis of chiral SPO was explored such as the readily available (1S,2R)-aminoindanol 16 that has been previously used in the synthesis of P-stereogenic phosphanamine and chiral sulfinamides.5b,11 Using the same protocol, treatment of 16 with PhPCl2 in THF at −78 °C yielded Sp-17a in high selectivity of >98:2 dr, and its stereochemistry was determined by the single-crystal X-ray of its oxidation product Sp-19 (Scheme 3). In situ treatment of Sp17a with water afforded Rp-18a in high selectivity of >98:2 dr. Rp-18a is a crystalline product, and one crystallization from EtOAc/hexanes yielded its enantiomerically pure form in 85%

a

Selectivity based on NMR analysis or LC/MS. bIsolated yield after recrystallization for enantiomerically pure product.

phosphinate products 18 can be obtained with good-toexcellent selectivities and high yields. Products with phenyl substituents (18b−e), naphthalene substituents, phenanthrenes (18f−h), heterocycles (18i), ferrocene (18k), and alkyl substituents (18j) all proceeded with high selectivities and were readily prepared. All of the reaction products were crystalline, and their optically pure forms were readily obtained via a single crystallization and prepared on multigram scale. The synthesis of P-stereogenic SPOs is straightforward using the above protocol of treatment of 18 with t-BuLi in THF. Clean reactions were observed in all cases (Table 1). The scope of the P-stereogenic SPOs products that can be synthesized range from ones containing phenyl with diverse substituents (3b−e), polycyclic aromatics (3f−h), and even heterocyclesubstituted (3i) and dialkyl SPO (3j). It should be noted that the hindered 3g was accessed previously only by chromatographic separation.10c The efficient synthesis of chiral phosphinates using readily available PCl3 and an organometallic reagent was next explored, and the success of this approach would avoid the synthesis of phosphine dichloride reagents such as ArPCl2 (Scheme 4). The stereochemistry of the process was first examined by the synthesis of 18d. Treatment of 16 with PCl3 in THF in the presence of pyridine at −78 °C for 2 h afforded 20, and its reaction with water afforded 21 in high isolated yield. Interestingly, treatment of 20 with 2-MeO-PhMgBr in situ followed by addition of water provided 18d in 82% yield and >85:15 dr. Recrystallization of crude 18d from EtOAc/hexanes afforded the enantiomerically pure Rp-18d with an (R)-

Scheme 3. Asymmetric Synthesis of 3a by Using 16

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DOI: 10.1021/acs.orglett.7b00568 Org. Lett. 2017, 19, 1796−1799

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Organic Letters Scheme 4. Synthesis of P-Stereogenic Phosphinates via PCl3 and an Organometallic Reagent

Use of these SPOs in the synthesis of P-stereogenic tertiary phosphine oxides (TPOs) by transition-metal-catalyzed coupling reactions was investigated. Transition-metal-catalyzed SPO coupling with aryl halides via P−C bond formation has been reported for the synthesis of racemic substrates,14 but few reports have dealt with the reactions of chiral nonracemic or sterically unhindered chiral SPOs.14b,c Our interest in the synthesis of chiral phosphine ligands with heterocycle functionality led us to explore the coupling of 2-bromopyridine 22 with chiral SPOs. Reaction conditions were surveyed first for the synthesis of 2a. Treatment of 22 with 3a in the presence of 5 mol % of Pd 2dba 3 and 20 mol % of dppp (1,3bis(diphenylphosphino)propane) in toluene gave a reaction that was only complete after 18 h at 110 °C. It afforded 2a in good isolated yield without enantiopurity erosion. Single-crystal X-ray analysis of 2f revealed that the reaction proceeded with retention of stereochemistry as observed by Herzon et al.14b Following this protocol, a variety of pyridine-containing Pstereogenic TPOs with diverse functionalities were readily prepared (Table 3). Moreover, very bulky TPOs such as 2e−g

configuration at phosphorus as confirmed by single-crystal Xray analysis. It was envisioned that Rp-18d was obtained through intermediate Sp-17d as described in Scheme 3, and therefore, it was rationalized that the configuration of 20,12a formed supposedly via N-tosylsulfonamide attacks on phosphorus from the less hindered side, was retained in the reaction with 2-MeO-PhMgBr as observed in a similar system by Xiao et al.12b Similarly, treatment of 11 with PCl3 followed by 2-MeOPhMgBr and water afforded phosphinate 14b in 94:6 dr and 71% isolated yield and in enantiomerically pure form after recrystallization (Table 2).

Table 3. Synthesis of Chiral TPOs via Coupling Reaction

Table 2. Synthesis of More Hindered P-Stereogenic SPOs

a 1.2 equiv of 22 used except where indicated. ber based on chiral HPLC analysis. cer of SPOs used for the reaction. d2.4 equiv of 22 used. e20 mol % of catalyst used.

were all obtained in high yields and excellent enantiomeric purities. The exceedingly bulky phosphine oxide 2h was also synthesized in excellent selectivity of 99.5:0.5 er albeit in diminished yield due to the severe steric hindrance. It is worth noting that the synthesis of such bulky P-stereogenic phosphine oxides was not possible using previously reported methods. We believe that the newly developed method should greatly facilitate the design and synthesis of more efficient Pstereogenic P,N ligands, which are an important class of phosphine ligand in catalysis.15 Furthermore, the synthesis of P-stereogenic bis-phosphine oxides was also achieved by using this coupling strategy. Reaction of 2,6-dibromopyridine with 3d afforded 23 in good yield and excellent selectivity. Subsequent reaction of 23 with another equivalent of 3d furnished bis-phosphine oxide 24 efficiently and in highly enantiomerically enriched form. The latter is a key precursor for the synthesis of a P-stereogenic P, N, P ligand (Scheme 5 (a)). Phosphine oxide 26 was also prepared successfully via this method, which can be used for the synthesis of P-stereogenic version of QUINAP type of P, N ligands (Scheme 5(b)). The application of SPOs in the synthesis of a phosphine ligand was demonstrated in the synthesis BI-DIME, which finds many applications in catalysis chemistry.3d,16 Following the

a

Isolated yield after recrystallization for enantiomerically pure products. bCombined yields for both diastereomers.13 See the Supporting Information for details. cPrepared from 13b.

This strategy was first applied for the synthesis of bulky Pstereogenic SPO tert-butyl(2,4,6-triisopropylphenyl)phosphine oxide 3l (Table 2). When either 11 or 16 was used, treatment with PCl3 followed by 2,4,6-triisopropyl-PhMgBr and water afforded the corresponding phosphinates 14c and 18l with excellent selectivity of >99:1 dr and 98:2 dr, respectively. Both compounds are crystalline products, and gram quantities of enantiomerically pure products were isolated in good yield after a single recrystallization. The subsequent reaction of 14c or 18l with t-BuLi provided the bulky 3l in high enantiomeric purity and good yield (Table 2). The scope of this approach was demonstrated in the synthesis of other chiral phosphinates 14d, 18g, and 18m in good-to-excellent selectivities, from which Pstereogenic SPOs such as 2-MeO-naphthalene 3m were prepared successfully in high stereoselectivities. 1798

DOI: 10.1021/acs.orglett.7b00568 Org. Lett. 2017, 19, 1796−1799

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Organic Letters Notes

Scheme 5. Synthesis of Phosphine Oxides Used for P,N Ligand Precursors

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Scott Pennino, Mr. Keith McKellop, and Dr. Fenghe Qiu of Boehringer Ingelheim, US, for HRMS analysis. (1) See recent references: (a) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029. (b) Hu, N.; Li, K.; Tang, W. Angew. Chem., Int. Ed. 2016, 55, 504. (c) Imamoto, T.; Tamura, K.; Zhang, Z.; Horiuchi, Y.; Sugiya, M.; Yoshida, K.; Yanagisawa, A.; Gridnev, I. D. J. Am. Chem. Soc. 2012, 134, 1754 and the references cited therein. (2) Lipkowitz, K. B.; D’Hue, C. A.; Sakamoto, T.; Stack, J. N. J. Am. Chem. Soc. 2002, 124, 14255. (3) For example: (a) Pietrusiewicz, K.; Zablocka, M. Chem. Rev. 1994, 94, 1375. (b) Grabulosa, A.; Granell, J.; Muller, G. Coord. Chem. Rev. 2007, 251, 25. (c) Xu, Q.; Zhao, C.-Q.; Han, L.-B. J. Am. Chem. Soc. 2008, 130, 12648. (d) Han, Z. S.; Goyal, N.; Herbage, M. A.; Sieber, J. D.; Qu, B.; Xu, Y.; Li, Z.; Reeves, J. T.; Desrosiers, J. N.; Ma, S.; Grinberg, N.; Lee, H.; Mangunuru, H. P. R.; Zhang, Y.; Krishnamurthy, D.; Lu, B. Z.; Song, J. J.; Wang, G.; Senanayake, C. H. J. Am. Chem. Soc. 2013, 135, 2474. (4) (a) Noonan, G. M.; Fuentes, J. A.; Cobley, C. J.; Clarke, M. L. Angew. Chem., Int. Ed. 2012, 51, 2477. (b) Hérault, D.; Nguyen, D. H.; Nuel, D.; Buono, G. Chem. Soc. Rev. 2015, 44, 2508. (5) (a) Wolfe, B.; Livinghouse, T. J. Am. Chem. Soc. 1998, 120, 5116. (b) Leon, T.; Riera, A.; Verdaguer, X. J. Am. Chem. Soc. 2011, 133, 5740. (c) Gatineau, D.; Giordano, L.; Buono, G. J. Am. Chem. Soc. 2011, 133, 10728 and references cited therein. (6) Recent reviews: (a) Schwan, A. L. Chem. Soc. Rev. 2004, 33, 218. (b) Shaikh, T. M.; Weng, C. M.; Hong, F. Coord. Chem. Rev. 2012, 256, 771. (7) (a) Xu, P.; Wu, Z.; Zhou, N.; Zhu, C. Org. Lett. 2016, 18, 1143. (b) Jaklinska, M.; Cordier, M.; Stankevic, M. J. Org. Chem. 2016, 81, 1378. (c) Zhu, Y.; Chen, T.; Li, S.; Shimada, S.; Han, L.-B. J. Am. Chem. Soc. 2016, 138, 5825 and references cited therein. (8) (a) Kortmann, F. A.; Chang, M.-C.; Otten, E.; Couzijn, E. P. A.; Lutz, M.; Minnaard, A. J. Chem. Sci. 2014, 5, 1322. (b) Gatineau, D.; Nguyen, D. H.; Hérault, N. D.; Vanthuyne, N.; Leclaire, J.; Giordano, L.; Buono, G. J. Org. Chem. 2015, 80, 4132. (c) Copey, L.; JeanGérard, L.; Andrioletti, B.; Framery, E. Tetrahedron Lett. 2016, 57, 543. (9) (a) Zhang, H.; Sun, Y.-M.; Yao, L.; Ji, S.-Y.; Zhao, C.-Q.; Han, L.B. Chem. - Asian J. 2014, 9, 1329. (c) Bloomfield, A. J.; Herzon, S. B. Org. Lett. 2013, 14, 4370. (10) (a) Ackermann, L.; Born, R.; Spatz, J. H.; Meyer, D. Angew. Chem., Int. Ed. 2005, 44, 7216. (b) Ackermann, L.; Vicente, R.; Hofmann, N. Org. Lett. 2009, 11, 4274. (c) Gasparrini, F.; Lunazzi, L.; Mazzanti, A.; Pierini, M.; Pietrusiewicz, K. M.; Villani, C. J. Am. Chem. Soc. 2000, 122, 4776. (11) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake, C. H. J. Am. Chem. Soc. 2002, 124, 7880. (12) (a) The stereochemistry is predicted from the reaction with PhPCl2 as described in Scheme 3. (b) Vinci, D.; Mateus, N.; Wu, X.; Hancock, F.; Steiner, A.; Xiao, J. Org. Lett. 2006, 8, 215. (13) The minor diastereomer crystallized first, and the major diastereomer was isolated from the mother liquor by removing the minor one. (14) (a) Uozumi, Y.; Tanahashi, A.; Lee, S. Y.; Hayashi, T. J. Org. Chem. 1993, 58, 1945. (b) Bloomfield, A. J.; Herzon, S. B. Org. Lett. 2012, 14, 4370. For reviews, see: (c) Tappe, F. M.; Trepohl, V. T.; Oestreich, M. Synthesis 2010, 2010, 3037. (d) Chen, T.; Han, L.-B. Synlett 2015, 26, 1153 and references cited therein. (15) (a) Carroll, M. P.; Guiry, P. J. Chem. Soc. Rev. 2014, 43, 819. (b) Smirnova, E. S.; Munoz Molina, J. M.; Johnson, A.; Bandeira, N. A. G.; Bo, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2016, 55, 7487. (16) Xu, G.; Fu, W.; Liu, G.; Senanayake, C. H.; Tang, W. J. Am. Chem. Soc. 2014, 136, 570.

reaction shown in Scheme 6,8a 3e was converted to 29, a key precursor for BI-DME, in high yield with high enantiomerica purity (Scheme 6). Scheme 6. Synthesis of BI-DIME Precursor

In summary, a general and stereoselective methodology has been developed for the synthesis of P-stereogenic chiral SPOs. The method relies on the efficient synthesis of chiral secondary phosphinates using the readily available amino alcohols as chiral templates. These chiral phosphinates are readily prepared on a multigram scale, from which a variety of sterically hindered and structurally diverse chiral SPOs were prepared. The chiral templates can be recovered after the reaction and can be reused. These SPOs were successfully employed for the synthesis of hindered TPOs with high stereospecificities. We believe that this method offers a new avenue for the design and synthesis of versatile P-stereogenic chiral phosphine ligands for asymmetric catalysis, and these and other related applications are under investigation in our laboratories.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00568. Experimental procedures, detailed reaction condition survey results, and spectroscopic data for all new compounds (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Zhengxu S. Han: 0000-0001-8386-1356 Keith R. Fandrick: 0000-0003-4875-3143 1799

DOI: 10.1021/acs.orglett.7b00568 Org. Lett. 2017, 19, 1796−1799